Project Summary The US opioid epidemic continues to evolve with highly potent synthetic opioids (HPSO) now driving higher overdose fatality rates. There has been a five-fold increase in US synthetic opioid overdose rate from 2013 (3,105) to 2016 (approximately 20,000) out of the approximately 42,000 overdose deaths due to opioids. Fentanyl analogs and other HPSO are now commonly found in heroin and counterfeit prescription painkiller pills. Due to the rapidly changing nature of the illicit drug supply, the efficacy of commonly used pharmacotherapies for opioid use disorder (OUD) (e.g., buprenorphine, methadone, naltrexone) in treating users of HPSO is unknown. The increasing number of overdose deaths combined with possible lower efficacy of standard therapies creates an urgent need to develop new strategies for the HPSO-using patient. Despite the known effectiveness of buprenorphine sublingual (BSL) maintenance treatment, retention and continued non-prescribed opioid use remain significant limitations, with approximately 50% or more of patients treated with BSL dropping out of treatment by 3 to 6 months. The first extended-release injectable buprenorphine (Sublocade?) became commercially available in 2018 after FDA Fast Track and Priority Review designation. This monthly buprenorphine formulation, which is available in two doses (100 mg and 300 mg), can achieve serum buprenorphine concentrations in excess of that achieved by BSL 24 mg per day. Moreover, if an unexpected drug holiday is experienced, at two weeks past the injection due date, -opioid receptor remains above 70%, providing extended protection against opioid withdrawal and relapse. While this buprenorphine extended-release (BXR) injection formulation has not yet been compared to BSL treatment, the pharmacologic advantages of an extended-release injection can be expected to improve treatment retention and outcomes. The extended-release injection aspect should improve compliance and reduce relapse by providing more continuous buprenorphine serum levels as compared to the sublingual formulation. We hypothesize that BXR injection will have particular benefit for individuals using fentanyl analogues because by providing continuous therapeutic serum buprenorphine levels there will be substantially less opportunity for non-compliance and relapse. Individuals who discontinue BSL and use HPSO containing opioids may have more difficulty restarting sublingual treatment, leading to treatment failure. We propose an early Phase II clinical trial, in which patients seeking treatment for OUD who are positive for HPSO at screening (N = 40) will be inducted onto BSL and then randomly assigned to receive either standard therapy (BSL maintenance) or BXR injection, under open label conditions, with a primary outcome measure of days of opioid use per week as measured by the timeline followback method confirmed by urine toxicology. To our knowledge, this would be the first trial testing a treatment for individuals with OUD using HPSO.